Cystic Fibrosis: It Keeps Progressing

28. December 2017

Until now, cystic fibrosis has been primarily treated symptomatically. Now results exist from studies on causal therapy: tezacaftor, a new "CFTR corrector", can improve the lung function of patients when combined with ivacaftor. Is this really a step forward?

In Germany, one in every 2,500 newborns suffers cystic fibrosis. Over time screening for this most often fatal congenital metabolic disease has become standard procedure. Doctors look among other things for mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. In patients with this disease, there are some cells which only develop defective chloride channels. If not enough water from the surrounding tissue gets into the exocrine glands, secretions become viscous and organs no longer perform their tasks properly. In recent decades patients have been successfully and ever better provided with pharmaceuticals, physical therapies, diets and sports options. These successes cannot be denied. Nevertheless, life expectancy is barely more than 40.

Symptomatic therapy

This is due to the impairment of various organ systems. Problems especially often occur in the bronchi. The ciliated epithelium cannot properly transport viscous mucus. Patients suffer from cough and recurrent serious infections. Bacteria such as Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia cepacia and Haemophilus influenzae make themselves at home in patients’ biofilm. Recurrent bronchitis and pneumonia occur. Bronchiectasis is also typical, in other words severe dilatations of the bronchi and inflammatory processes.

In order to dissolve the mucus, patients are supposed to regularly inhale saline, acetyl cysteine or ambroxol. Used as an adjunct, the enzyme recombinant human DNase has proven its capacity to split neutrophil granulocytes in the mucus. These originate from already decayed infections. If the fragments get degraded, viscosity is reduced. With recurrent infections doctors prescribe high-dose antibiotics.

Bronchodilators such as ipratropium bromide, salbutamol and fenoterol improve lung function. With increasing lung dysfunction the only remaining option is long-term oxygen therapy.

Moreover the pancreas in cystic fibrosis sufferers also does not work properly. Patients suffer from chronic diarrhoea and fatty stools. Since nutrients are not properly utilised, being underweight is the usual experience. High calorie diets improve the situation, in combination with digestive enzymes. If ileus occurs, surgical help is required. Since connective tissue gets increasingly deposited into the pancreas, this can lead to cystic fibrosis related diabetes (CFRD), a form of Type 3 diabetes. Endocrinologists prescribe insulin as promptly as possible.

Why osteoporosis occurs as a late complication of cystic fibrosis is something which cannot be answered conclusively. It’s not just due to malabsorption. Bone-depleting osteoclasts are significantly more active than in healthy people. Their adversary, the bone-building osteoblasts, produce defective CFTR protein. This presumably leads to a disordered balance between osteoprotegerin and prostaglandin E2, and consequently to greater bone resorption. From a therapeutic perspective, medications used in osteoporosis therapy, for example bisphosphonates, strontium and teriparatide, are suitable as treatment.

In search of healing

All approaches have the aim of alleviating symptoms. This makes the desire for causal therapies all the greater. In 2015, Eric Alton from the Royal Brompton and Harefield NHS Foundation Trust, London, showed that gene therapy is possible in principle. Results from his phase 2 study however fell far short of expectations. Patients reported only a slight improvement in their lung function compared to placebo.

Alton worked in the classic manner using a plasmid to introduce intact CFTR genes into cells. Whether the much-discussed “gene shear” CRISPR / Cas9 can lead to better results is an open question. Currently, lung transplants remain one way out of the problem, although long-term success here is controversial among scientists. Due to the lack of donor organs, this treatment is only suitable for the most severe cases anyway.

Show me your genome

Researchers have now succeeded in developing pharmaceutics which repair defective CFTR proteins to a certain extent. What is involved here is the use of patient-specific approaches that are strongly based on the respective mutation:

Class 1: Patients no longer produce functional CFTR proteins.

Class 2: Cells do form CFTR proteins. However, these have different spatial structures and are therefore rapidly disposed of in the cell.

Class 3: Proteins are transported correctly to the cell membrane, however are not permeable to chloride ions.

Class 4: Proteins are transported correctly to the cell membrane, but are only partly permeable to chloride ions.

Class 5: Too little protein is produced, which may be due to alternative modifications after biosynthesis.

In 2012 the introduction of ivacaftor launched the era of personalised therapies. The molecule was approved for use on a rare class 3 mutation (G551D, a mutation at 551). Ivacaftor influences the defective chloride ion channel by causing it to open for longer. This brings with it an increased probability of chloride transport occurring through the channel.

At 71.8 percent frequency, the more severe class 2 mutation ΔF508 is significantly more relevant. The amino acid phenylalanine is missing at position 508. Ivacaftor on its own does not lead to the desired effect. That’s why researchers had an idea. They combined two pharmaceutical agents with differing properties. Functioning as a “corrector”, lumacaftor stabilises the protein and ensures that it has the right spatial structure. The protein reaches the cell membrane without a permeable channel developing. Only the “activator” ivacaftor opens the channel.

“The therapy however has several disadvantages”, Hartmut Grasemann from the University of Toronto writes. “The effect is modest, probably due to interactions of both treatment agents”. Ivacaftor and lumacaftor are both degraded by cytochrome P450-3A4 enzymes. In addition, dyspnea, liver damage and interactions with other drugs can all occur, he says.

Make three out of two

Now researchers are presenting results from studies on tezacaftor, a new “proofreader”. This molecule was studied along with ivacaftor in two manufacturer-funded phase 3 studies. All patients had the frequent ΔF508 mutation.

The EVOLVE study involved the participation of 509 patients aged 12 and over. They received tezacaftor plus ivacaftor or placebo. After 24 weeks, 475 had completed the study. Lung function improved with the verum as measured in terms of one-second capacity (FEV1); by 4.0% in absolute terms, and in relative terms by 6.8%. Exacerbations occurred 35% less frequently.

We also have results from the second study, EXPAND. 162 patients aged 12 years or older received tezacaftor plus ivacaftor; 157 received ivacaftor only and another 162 a placebo. After eight weeks the FEV1 measures compared to placebo improved by 6.8 percent (combination) and by 4.7 percent (ivacaftor).

In both studies, adverse reactions were usually mild or moderate. These included exacerbations with haemoptysis, fever, headache, infections, inflammation of the nose and throat, fatigue and production of more sputum. However, looking at both EVOLVE and EXPAND it remains unclear whether tezacaftor alone or in combination with ivacaftor works better than the already approved combination lumacaftor/ivacaftor. A comparison-group has been lacking so far. Despite unanswered questions, Vertex has now sought approval in the USA and Europe. At the same time, the manufacturer wants to investigate combinations of three active molecules .

Everything has its price

Feelings of hope are not the only thing raised by the therapeutic agents belonging to the CFTR-potentiators class. According to a Joint Federal Committee the additional beneficial uses of lumacaftor/ivacaftor are indeed “noteworthy”. However, this is offset by the price of around 200,000 euros for one-year of therapy. As a comparison: medicines used in standard treatment costs € 21,000 per patient per year. And lung transplants – assuming donor organs are at hand – cost about 150,000 euros.